Anti-LPS antibody for Pediatric Nonalcoholic Fatty Liver Disease

项目摘要 非酒精性脂肪性肝病（NAFLD）是一种慢性肝病，影响美国10 - 30%的儿童。 states. NAFLD在儿童中具有惊人的侵袭性，目前还没有批准的治疗方法。 NAFLD的发病通常发生在幼儿（8 - 12岁），任何潜在的NAFLD治疗方法都需要 几乎没有风险在本提案中，我们寻求研究IMM-124E，一种最初开发的医疗产品， 治疗旅行者腹泻，在澳大利亚已经有很多年的非处方药了。IMM-124E是一种 高度免疫的牛初乳，通过干燥牛的第一次乳汁并将其包装成囊片而制成。这 超免疫"奶粉"富含抗E.大肠杆菌的细菌产物（LPS）， 怀孕的母牛由于微生物组的改变、肠道通透性的增加和LPS的增加已被证明是 IMM-124 E在NAFLD的发病机制中起重要作用，IMM-124 E对NAFLD的疗效具有逻辑支持。i期研究 在成年人中显示出改善的胰岛素抵抗、肝酶和促进调节性T细胞。这 该提案旨在测试IMM-124E在NAFLD儿童中的小型II期研究，以评估 初步疗效和安全性终点，并提高对机制的理解。这将是 在一项为期12周的双盲、随机、安慰剂对照临床试验中， NAFLD儿童目的1将确定用IMM-124E与以下药物组合治疗3个月是否有效： 生活方式改变（护理标准（SOC））导致1）肝脂质和炎症的更大改善， 2)胰岛素敏感性，3）血脂，NAFLD儿童，与安慰剂相比，SOC以及监测 安全性相关终点。目标2将定义作用相关终点的机制，包括：粪便微生物组， 代谢组学，LPS和先天免疫反应基因的转录组学，并将这些与 临床测量该提案利用了埃默里大学最先进的平台，包括高 高通量、高分辨率代谢组学和已建立的微生物组和转录组学中心， 完成机理研究。此外，我们有临床人群，可以快速招募儿童进入 这次审判该提案通过严格调查一项与国家卫生研究院、国家儿童健康中心和国家儿童健康与发展研究所的使命有关的 补充治疗有可能改善大量儿童的健康状况。如果成功，这些 研究将支持设计未来的大规模III期试验。这些研究将增进我们对 肠道在儿童NAFLD中的作用，如果阳性，将导致低风险，低副作用，高产量 治疗小儿NAFLD。

Project Summary Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that affects 10-30% of children in the United States. NAFLD is surprisingly aggressive in children and there is currently no approved therapy for it. Because the onset of NAFLD is often in young children (8-12 years), any potential therapeutic for NAFLD will need to be almost risk-free. In this proposal, we seek to study IMM-124E, a medical product that was initially developed for traveler’s diarrhea and has been available over the counter in Australia for years. IMM-124E is a hyperimmune bovine colostrum manufactured by drying the cow’s first milk and packaging it into caplets. This hyperimmune “milk powder” is enriched with IgG against E. coli bacterial products (LPS) by vaccinating the pregnant cow. Because altered microbiome, increased gut permeability, and increased LPS have been shown to be important in the mechanism of NAFLD, IMM-124E has logical support for efficacy in NAFLD. Phase I studies in adults have shown improved insulin resistance, liver enzymes, and promotion of regulatory T-cells. This proposal is designed to test IMM-124E in a small phase II study in children with NAFLD in order to assess preliminary efficacy and safety endpoints and to improve understanding of the mechanisms. This will be accomplished through two aims in a 12 week double-blind, randomized, placebo-controlled clinical trial in children with NAFLD. Aim 1 will determine if 3 months of treatment with IMM-124E in combination with lifestyle changes (standard of care (SOC)) results in greater improvement in 1) hepatic lipid and inflammation, 2) insulin sensitivity, 3) blood lipids, in children with NAFLD, compared to placebo with SOC as well as monitor safety related endpoints. Aim 2 will define mechanisms of action-related endpoints including: stool microbiome, metabolomics, LPS and transcriptomics of innate immune response genes and correlate these with changes in clinical measurements. The proposal leverages state-of-the art platforms at Emory University including high throughput, high resolution metabolomics and established centers for microbiome and transcriptomics to accomplish the mechanism studies. Additionally, we have the clinical population to quickly enroll children into this trial. This proposal addresses the mission of the NIH NCCIH and NICHD by rigorously investigating a complementary treatment with the potential to improve health for large numbers of children. If successful, these studies would support designing a future large scale phase III trial. These studies will enhance our understanding of the role of the gut in pediatric NAFLD and if positive, will result in a low risk, low side effect, high yield therapeutic for pediatric NAFLD.